Desquamative interstitial pneumonia: an analytic review with an

Eur Respir Rev 2013; 22: 128, 117–123
DOI: 10.1183/09059180.00005812
CopyrightßERS 2013
REVIEW
Desquamative interstitial pneumonia:
an analytic review with an emphasis
on aetiology
Benoı̂t Godbert*, Marie-Pierre Wissler# and Jean-Michel Vignaud#
ABSTRACT: Desquamative interstitial pneumonia (DIP) is characterised by the accumulation of
numerous pigmented macrophages within most of the distal airspace of the lung and, sometimes,
the presence of giant cells. Diagnosis of DIP is not easy and requires surgical lung biopsy. DIP is
usually associated with tobacco smoke. However, the association between smoking and DIP is
less robust than that with respiratory bronchiolitis with interstitial lung disease or pulmonary
Langerhans’ cell histiocytosis; approximately 10–42% of patients with DIP are nonsmokers. DIP
can also occur in patients following exposure to certain inhaled toxins (occupational exposure)
and drugs, and may occur in the context of certain viral illnesses and autoimmune diseases. In the
context of DIP, occupational exposure should be systematically investigated.
KEYWORDS: Giant cell, interstitial lung disease, macrophages, occupational lung disease,
surgical lung biopsy, tobacco
esquamative interstitial pneumonia (DIP)
was described by LIEBOW et al. [1] in 1965.
Its name originated from the belief that
the dominant histological feature was desquamation of epithelial cells [1, 2]; however, this is now
recognised to be the accumulation of intra-alveolar
macrophages, sometimes associated with giant
cells [3]. Despite the inaccuracy of this term, the
American Thoracic Society and European Respiratory Society have retained the term DIP, mainly
because of this disease’s rarity [4].
D
It is now fairly certain that DIP is very often
associated with cigarette smoke and even with
passive exposure. The incidence in smokers
ranges from 58% to 91% [3, 5, 6]; thus, many
patients with DIP are cigarette smokers. However,
DIP is more frequently seen in nonsmokers
than respiratory bronchiolitis associated with
interstitial lung disease (RB-ILD), and has also
been observed in pneumoconiosis, rheumatological disease and some drug reactions [7–9].
Thus, DIP is not always associated with exposure to tobacco smoke: occupational exposure to
other agents should also be considered to avoid
disregarding an occupational aetiology. In this
article, we systematically review DIP and, in
particular, the association between occupational
exposure and DIP.
EUROPEAN RESPIRATORY REVIEW
EPIDEMIOLOGICAL AND CLINICAL
FEATURES
The average age at onset of symptoms of DIP is
between 40 and 60 years [1, 3, 5, 6]. Most studies
note a predominance of male patients, i.e. a 2:1
ratio to females [1, 3, 5, 6]. The most frequent
presenting features of DIP are the onset of breathlessness during exercise and a persistent cough
that is not always productive of sputum [1, 3, 5, 6].
Chest pain and systemic symptoms, including
weight loss and fatigue, can also be present [1, 3, 5,
10]. Haemoptysis is rarely described [1, 3].
Occasionally, DIP may be diagnosed in an
asymptomatic individual [3, 5, 6]. Bibasilar endinspiratory crackles and cyanosis are frequently
present, and clubbing is not rare [1, 3, 5, 6, 10].
Thus, DIP is classically characterised by an
insidious onset of symptoms but may present as
a fulminant or rapidly progressive disease [11–13].
The epidemiological and clinical features of DIP
are summarised in table 1.
PULMONARY FUNCTION TESTS
Pulmonary restriction is usually absent or slight,
although diffusion is impaired in most patients
with DIP [1, 3, 5, 6]. In the first description of DIP
by LIEBOW et al. [1], total lung capacity was ,80%
predicted in only two out of 10 patients; in a
study by YOUSEM et al. [5] mean total lung
VOLUME 22 NUMBER 128
AFFILIATIONS
*CHU de Nancy, Pôle de spécialités
médicales, Service de pneumologie,
Nancy, and
#
CHU de Nancy, Pôle laboratoires,
Service d’anatomo-pathologie,
Nancy, France.
CORRESPONDENCE
B. Godbert
Service de Pneumologie
Bâtiment Philippe Canton
Hôpitaux de Brabois-CHU de Nancy
Avenue de Bourgogne
54511 Vandoeuvre-les-Nancy cedex
France
E-mail: [email protected]
Received:
Sept 25 2012
Accepted after revision:
Oct 23 2012
PROVENANCE
Submitted article, peer reviewed.
European Respiratory Review
Print ISSN 0905-9180
Online ISSN 1600-0617
c
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REVIEW: DESQUAMATIVE INTERSTITIAL PNEUMONIA
TABLE 1
B. GODBERT ET AL.
Epidemiological and clinical features of desquamative interstitial pneumonia
LIEBOW [1]
Cases n
Males/females n
Age at onset years median
TUBBS [3]
YOUSEM [5]
RYU [6]
Total
18
26
36
23
103
10/8
17/9
26/10
11/12
64/39
45 (16–63)
51 (24–75)
42 (17–67)
46 (26–69)
46 (16–75)
NS
15/26 (58)
30/33 (91)
20/23 (87)
65/82 (79)
o10
36 (10–71)
31 (10–90)
NS
NS
(interquartile range)
Smoking history
Mean smoking exposure
pack-years (95% CI)
Occupational history, cases
exposed
1 exposed to plastic
No environmental
fumes and dusts
exposure or underlying
2 exposed to hairsprays
disease identified
Symptoms
Dyspnoea
18/18 (100)
23/26 (88.5)
29/34 (85)
20/23 (87)
Cough
14/16 (87.5)
18/26 (75)
26/32 (81)
10/23 (43)
90/101 (89)
68/97 (70)
Sputum
4/16 (25)
NS
17/33 (52)
NS
21/49 (43)
Weight loss
6/10 (60)
1/26 (4)
NS
NS
7/36 (20)
Chest pain
9/12 (75)
1/26 (4)
NS
4/23 (17)
14/61 (23)
Haemoptysis
1/18 (5.5)
2/26 (8)
NS
NS
3/44 (7)
Asymptomatic
0/18 (0)
1/26 (4)
5/34 (15)
1/23 (4)
7/101 (7)
Cyanosis
7/10 (70)
3/26 (11.5)
NS
NS
10/36 (28)
Crackles
,50%
17/26 (65)
5/9 (56)
13/23 (57)
35/58 (60)
Clubbing
5/9 (55.5)#
12/26 (46)
15/36 (42)#
6/23 (26)
38/94 (40)
Physical signs
Data are presented as n/N (%), unless otherwise stated.
NS:
not specified. #: clubbing sometimes disappeared after steroid therapy.
capacity was 94% (range 43–133%). At rest, as during exercise,
gas exchange is mostly impaired because alveolar–arterial
oxygen pressure is increased [1]. Indeed, in the description of
DIP by LIEBOW et al. [1], systemic arterial saturation at rest was
,95% in eight out of 10 subjects and oxygen saturation
diminished in all after mild exercise. In addition, the difference
between alveolar–arterial oxygen pressure was elevated in all
five patients in whom it was measured, ranging from 13 to
53 mmHg [1]. In the same study, carbon monoxide diffusing
capacity was tested in seven patients and was found to be
sharply reduced in six [1]. In the study by YOUSEM et al. [5],
mean carbon monoxide diffusing capacity was 45% pred
(range 32–78% pred). Significant obstructive impairment
(forced expiratory volume in 1 s (FEV1)/forced vital capacity
(FVC) ,70%) is uncommon in DIP and is probably attributable
to coexistent chronic bronchitis [3]. Cor pulmonale is rare [14].
BIOLOGICAL ANALYSES
Biological analyses of DIP (blood cell count, sedimentation rate,
renal function, liver function, immunological analysis, etc.) have
been generally unrewarding. Where data are presented in
published studies, they do not reveal specific significant
abnormalities for DIP [1], although LIEBOW et al. [1] found
polycythaemia in six out of 16 cases caused by respiratory
insufficiency. In general, levels of C-reactive protein are not
described. Serum lysozyme level has been reported to be
elevated some of the time [15]. Bronchoalveolar lavage fluid
invariably contains increased numbers of alveolar macrophages,
a large proportion of which have granules of ‘‘smoker’s
pigment’’ consisting of intracellular yellow, golden-brown or
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VOLUME 22 NUMBER 128
black particles [16]. Increased numbers of neutrophils, eosinophils and lymphocytes have also been found [17–19], but these
findings are not very specific.
RADIOLOGICAL FEATURES
The appearance of chest radiographs is often normal and any
abnormalities tend to be limited and nonspecific [1, 4].
Reported radiographic signs of DIP include widespread,
patchy ground-glass opacification, with a greater predilection
for the lower-lung zone and, sometimes, peripheral predominance [1, 4]. The ground-glass opacification sometimes has a
granular or nodular texture [20]. Because of the low prevalence
of DIP, its identification by high-resolution computed tomography (HRCT) has been only characterised in one small series
(n522) [21]. Ground-glass attenuation was present on the
computed tomograms of all of the 22 cases and was bilateral
and moderately symmetric in o550% of these cases. It had a
lower-zone distribution in the majority (73%) of cases, a
peripheral distribution in 59% of cases and was patchy in 23%
(figs 1 and 2). Distribution was diffuse and uniform in 18%.
Irregular and linear opacities and reticular patterns were
frequent (59%) but were limited in extent and usually confined
to the base of lungs. They were associated with anatomical
distortion, traction bronchiectasis and small peripheral cystic
spaces, which are believed to represent dilated bronchioles and
alveolar ducts. Honeycombing was seen in less than one-third
of cases, and was usually peripheral and limited in extent [21].
KAWABATA et al. [19] suggest that DIP may progress to lung
fibrosis. Indeed, long-term follow-up of 14 patients (mean
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B. GODBERT ET AL.
REVIEW: DESQUAMATIVE INTERSTITIAL PNEUMONIA
around a variety of spaces that occupy pulmonary lesions and of
some diffuse pulmonary disorders further limit the diagnostic
application of small-tissue biopsies: this mandates close radiographic correlation with findings from a surgical lung biopsy to
avoid over-diagnosis of DIP or RB-ILD [23, 24]. Thus, the
diagnosis of DIP requires a surgical lung biopsy (thoracoscopic
or open-lung procedure).
a)
HISTOLOGICAL FEATURES
Histological features were initially described by LIEBOW et al. [1].
Gross features
Surgeons have described the DIP lung as stiff, indurated and
somewhat nodular in some cases. In some parts, a coarser
porosity than usual gives the scattered foci a finely honeycombed appearance, and the tissue completely lacks the soft,
spongy characteristics of a normal lung [1].
Histology
DIP’s main feature is the presence of large numbers of
macrophages within alveoli that have a diffuse distribution
throughout the pulmonary acini [4, 5, 24]. These macrophages
have abundant eosinophilic cytoplasm and often contain a
finely granular light-brown pigment [5]. The presence of a few
multinucleated giant cells is common [1, 3]. The alveolar
architecture is generally well maintained, although there is
mild chronic inflammatory infiltrate within the interstitium. A
moderate number of eosinophils may also be seen. Lymphoid
aggregates may be present (fig. 2a–c) [1, 3, 4]. Interstitial fibrosis
is usually mild. If present, loss of architecture and cystic airspace formation appear closer to emphysema than to the
honeycomb change seen in usual interstitial pneumonia [25].
b)
In the absence of contraindications, the appearance of extensive
ground-glass attenuation on HRCT and the bronchoalveolar
lavage are both nonspecific, and according to the guidelines of
the American Thoracic Society/European Respiratory Society
and the British Thoracic Society, a surgical biopsy is advised in
patients with suspected idiopathic interstitial pneumonia who
does not show classic clinical and HRCT images of usual
interstitial pneumonia [4, 22]. Indeed, the subtle distinction
between macrophage distribution and intensity, and the
patterns of interstitial fibrosis across the secondary lobule, upon
which the diagnoses of RB-ILD and DIP are predicated, cannot
be achieved in the limited samples provided by a transbronchial
biopsy or core-needle biopsy. The presence of DIP-like reactions
Epidemiological studies suggest that ,58–91% of cases occur
in smokers and, in this context, DIP may be regarded as an
excessive response to tobacco smoke. With the recognition of
RB-ILD, DIP has come under scrutiny and many believe that
RB-ILD and DIP comprise points along a spectrum. The
histological findings for RB-ILD are an exaggerated inflammatory reaction with a marked increase in macrophages in and
around respiratory bronchioles and minor interstitial thickening (fig. 2d–f). In theory, DIP shows uniform diffuse airspace
filling by macrophages, with mild interstitial thickening and a
mild chronic inflammatory infiltrate. In practice, the changes
may not be entirely uniform. In given cases, one can find fields
that qualify as RB-ILD and fields that qualify as DIP. However,
although RB-ILD is a disease of smokers, there are several
agents that can cause a DIP-like reaction, such as dust
inhalation [26, 27], drug reactions [28] and inborn errors of
metabolism like in Gaucher’s disease [29]. DIP is usually
distinguishable from usual interstitial pneumonia, organising
pneumonia, lymphoid interstitial pneumonia and diffuse
alveolar damage because the significant accumulation of
macrophages is not seen and other histopathological features
are absent but, in rare cases, an overlap exists between DIP and
nonspecific interstitial pneumonia. Indeed, JANKOWICH et al.
[30] described a series of 10 patients with combined fibrosis
and emphysema, in which two patients demonstrated a pattern
of interstitial lung disease, on biopsy, characterised by intraalveolar macrophage accumulation in association with marked
alveolar septal fibrosis, consistent with a variant form of DIP
with extensive fibrosis. Furthermore, KAWABATA et al. [19]
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VOLUME 22 NUMBER 128
FIGURE 1.
Example of thin parenchymal section computed tomography
findings in desquamative interstitial pneumonia: patchy ground-glass attenuation
with a peripheral bilateral and almost symmetric distribution, and irregular and linear
opacities.
125 months) by HRCT showed the development of new thinwalled cysts and honeycombing in five patients [19].
119
c
REVIEW: DESQUAMATIVE INTERSTITIAL PNEUMONIA
B. GODBERT ET AL.
a)
b)
c)
d)
e)
f)
FIGURE 2.
a–c) This lung biopsy from a 55-year-old male patient, who was a nonsmoker, shows a typical desquamative interstitial pneumonia pattern. Tissue sections
show a) diffuse involvement of the lung by intense macrophage accumulations within almost all of the distal airspace, b) without significant thickening of alveolar septa and
sparse inflammatory infiltrate (*). Macrophages do not contain dusty pigment. c) Immunohistochemical analysis with CD163 antibody shows the macrophage nature of the
cells. d–f) Lung biopsy from a 66-year-old female, who was a heavy smoker, showing a respiratory bronchiolitis/interstitial lung disease pattern. d) Macrophage accumulation
is diffuse but predominantly peribronchiolar and f) in respiratory bronchioles. Alveolar septa are slightly thickened. e) The cytoplasm of most macrophages contains an
abundant dust-brown pigment.
suggest that DIP may progress to lung fibrosis (radiological
data).
Giant-cell interstitial pneumonia is DIP-like with more
numerous multinucleated giant cells. It is associated with
occupational exposure to hard metal dust; thus, occupational
exposure should be explored and systematic mineralogical
analysis of a biopsy sample is warranted though is not
absolutely necessary for diagnosis.
AETIOLOGIES OF DIP
Radiological support for smoking-related interstitial lung
disease was initially provided by WEISS [31, 32] and others,
who found that a mild degree of ‘‘diffuse pulmonary fibrosis’’
was three times more common in smokers than in nonsmokers.
Most authors have almost invariably associated DIP with
smoking [4, 5, 21, 23, 33–35], although DIP is sometimes
present in nonsmokers. In the series of CRAIG et al. [9], 40% of
20 patients were lifelong nonsmokers, yet in an older series of
TUBBS et al. [3], 42% of 26 patients had no history of cigarette
smoking. These findings suggest other aetiologies for DIP:
environmental exposure to inorganic particles is a recognised
cause of DIP [1, 8]. Thus, ABRAHAM and HERTZBERG [8]
conducted a study in 1981 on 62 cases of biopsy specimenproven cases of DIP. The biopsies were explored for inorganic
particles by scanning electron microscopy and all inorganic
particles were individually analysed using energy-dispersive
X-ray analysis. Of the 17 cases quantitatively analysed, there
were mean¡SEM 5.86107¡1.16107 particles per cm3 and
0.86106¡0.636106 particles per cm3 in controls (n55)
(p,0.001) [8]. Among the 17 patients, seven had an occupational history compatible with exposure to inorganic particles,
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VOLUME 22 NUMBER 128
and high concentrations of inorganic particles were found in
their biopsies [8]. Thus, these authors showed that ,75% (of
those with an available environmental history) had a history of
dust or fume exposure, and that specific types of particle
exposure were documented in 92% of cases. These findings
show an association between DIP and exposure to some
particles, suggesting an aetiological relationship [8].
Among 20 patients in a study by CRAIG et al. [9], two of the
eight nonsmokers and one patient in the smoker group had
been exposed to occupational dust as fire-extinguisher
powder, diesel fumes, and beryllium and copper dust,
respectively. In addition, MOON et al. [10] described a case of
DIP in a nonsmoking patient who was exposed to solder fumes
at work. However, there is no proof of a link between this
occupational exposure and the occurrence of DIP; however, in
light of the study by ABRAHAM and HERTZBERG [8], we can
suggest that this link is highly probable.
Another occupational cause of DIP could be exposure to nylon
filaments in textile works. Indeed, LOUGHEED et al. [36]
described a series of five employees from a small textile plant
that employed 88 workers. Two of these five patients were exsmokers and three were never-smokers. The plant manufactured upholstery fabric by gluing finely chopped nylon
filament (‘‘flock’’) to cotton/polyester fabric using a latex
adhesive. Lung biopsy samples demonstrated DIP associated
with diffuse alveolar damage. The unusual clustering of these
cases within a small textile plant suggests a link with the
occupational environment [36]. The authors of this study
suggested a potential role for mycotoxins inhaled from the
work environment (aflatoxins from Fusarium spp. cultured
EUROPEAN RESPIRATORY REVIEW
B. GODBERT ET AL.
REVIEW: DESQUAMATIVE INTERSTITIAL PNEUMONIA
from specimens taken from the work environment) [37]. It is
reported that aflatoxins may be toxic to the lungs [36–41];
however, only one of these studies described interstitial lung
disease related to aflatoxin toxicity [36–42]. Thus, the imputability of aflatoxin remains very uncertain.
Another case of DIP has been described in a 38-year-old male
textile worker [42]. This was a biopsy specimen-proven case,
with severe restrictive syndrome: FEV1 and FVC were 55%
predicted, and FEV1/FVC was 99%. The patient was a heavy
smoker (50 pack-years) but after remaining off work for 5 weeks
and without changing his smoking practices he felt somewhat
better, and his FEV1 and FVC increased substantially to 84%
pred without any other treatment. This suggests the probable
role of toxins within his workplace [42]. Thus, DIP, in some
cases, could be an occupational disease of textile workers.
however, without treatment, ,60% of patients with DIP suffer
clinical deterioration [51]. In contrast, CARRINGTON et al. [51]
observed spontaneous improvement without treatment in
,20% of 32 patients, although whether improvement was
related to smoking cessation is unclear. The role of cytotoxic
and other immunosuppressive agents remains undefined but
successful use of these agents has been described [52].
Finally, DIP has been described in tungsten carbide production
in biopsy specimens, as reviewed by LIEBOW and CARRINGTON [2].
In occupation-associated DIP, cessation of exposure is necessary. Indeed, in the series of five patients studied by LOUGHEED
et al. [36], all patients left the workplace, and only two of the
five patients returned to work and both experienced a relapse.
Two patients improved upon leaving the workplace and did
not required steroid therapy whereas a clinical response to
steroids was slow in the three other cases: steroid therapy was
finally stopped after a mean of 17 months of therapy. Three of
the five patients had chronic respiratory insufficiency and two
remained oxygen dependent after exertion. Thus, steroid
therapy was not very efficient in these cases [36].
Thus, there is a strong hypothesis that DIP can be caused by
occupational exposure. We suggest that this should be
systematically explored, and think that mineralogical analysis
of biopsy samples is necessary when a case of occupationassociated DIP (exposure to inorganic dust) is suspected.
KNYAZHITSKIY et al. [53] suggest a possible role for macrolide
antibiotics in patients with DIP refractory to steroid therapy.
They described the first case of DIP showing a rapid and
dramatic response to treatment, in all clinical and radiographic
parameters, with clarithromycin.
In addition, DIP has been associated with connective tissue
disease [43, 44], rheumatoid arthritis [45], drugs such as
sirolimus [46], infection [47–49], and users of large amounts of
marijuana [50]. All known causes of DIP other than tobacco
smoking are summarised in table 2.
Transplantation is indicated for terminal respiratory insufficiency but recurrence in the transplanted lung has been
reported [54, 55]. Survival from DIP is evaluated to be between
68% and 94% [1, 4–6].
TREATMENT, RESPONSE TO TREATMENT AND
PROGNOSIS
Smoking cessation is probably an important and indispensable
component in the management of patients with DIP, but the
influence of smoking cessation on the clinical course has not
been delineated.
Patients treated for DIP usually receive long-term corticosteroid therapy [1, 5, 50]. With this treatment, most patients remain
stable or improve, and complete recovery is possible [5, 50];
TABLE 2
CONCLUSION
DIP is usually associated with exposure to tobacco smoke but
is sometimes present in nonsmokers, which strongly suggests
occupation-associated DIP. Thus, occupational exposure of
infectious or iatrogenic origins and connective tissue disease
should be systematically explored.
Little is known about the differences between occupationassociated DIP, smoke-related DIP and idiopathic DIP. We
found only one study that focused on the clinical differences
between smokers and nonsmokers with DIP: the authors were
All causes implicated in desquamative interstitial pneumonia (DIP), other than tobacco smoking
Causes
Occupational exposure to
Ref.
[1, 2 8–10]
inorganic particles
Comments
Nature of particles: Si, Mg, Ti, Fe, Ni, Pb, Cr, Au, Ag, Al, K, Ti, BaS, Be, Cu
Occupation: tool grinder, arc polisher, tyre manufacturing worker, plastic machinist, Al arc
welder, worker exposed to fire-extinguisher powder, diesel fumes
Exposure to mycotoxins
[37–43]
Connective tissue diseases
[44, 45]
Rheumatoid arthritis
Occupational exposure to aflatoxin (textile worker)
[46]
Sirolimus
[47]
Infection
[48–50]
DIP following concurrent CMV and Aspergillus pneumonias in a renal transplant recipient
(who did not receive sirolimus)
Association of DIP and HCV infection
Association of DIP and CMV infection in a baby
Use of marijuana
[51]
c
CMV: cytomegalovirus; HCV: hepatitis C virus.
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REVIEW: DESQUAMATIVE INTERSTITIAL PNEUMONIA
unable to identify any clinical differences [12]. Further multicentric observational studies with greater numbers of patients
are warranted to search for clinical, biological, radiological and
histological characteristic differences between occupationassociated DIP, smoke-related DIP and idiopathic DIP, if these
exist. Detailed and specific exploration of possible occupational exposure and smoking history (including exposure to
passive smokers) and systematic mineralogical analyses of
biopsy samples are needed.
STATEMENT OF INTEREST
None declared.
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